Anna F. Farago, MD, PhD, medical oncologist at the Center for Thoracic Cancers at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, discusses the use of frontline immunotherapy versus maintenance immunotherapy in patients with small cell lung cancer (SCLC).

Frontline chemotherapy combined with immunotherapy was tested in the phase III IMpower133 study and showed a benefit in overall survival (OS) and progression-free survival (PFS). However, investigators failed to report a benefit in response rates with the combination. This led to the belief that the true effect of immunotherapy came in the maintenance setting as opposed to the upfront setting.

However, the results of the phase III CheckMate-451 trial showed the opposite to be true. In the trial, patients were randomized to receive maintenance ipilimumab (Yervoy) plus nivolumab (Opdivo), nivolumab alone, or placebo following 4 cycles of first-line platinum etoposide. The primary endpoint of the trial was an OS comparison between the ipilimumab/nivolumab arm and the placebo arm. The results were negative, showing no difference in OS between the 2 arms.

Investigators did note a trend toward an improvement in survival with the nivolumab alone arm compared with placebo, especially among patients who started nivolumab within 5 weeks of completing chemotherapy, says Farago. Although these data suggest that there may be some benefit to single-agent PD-1/PD-L1 inhibitors in the maintenance setting, it is not robust enough to apply to practice. Instead, the combination of atezolizumab (Tecentriq) and standard chemotherapy is being used in the frontline setting, after which atezolizumab can be continued into the maintenance setting, concludes Farago.

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Dr. Farago on Frontline Immunotherapy Versus Maintenance Immunotherapy in SCLC

Anna F. Farago, MD, PhD, assistant professor of medicine at Harvard Medical School, discusses the phase II trial results using the marine-based drug lurbinectedin as a single-agent treatment in patients with small cell lung cancer (SCLC).

Lurbinectedin functions by inhibiting activated transcription in SCLC, explains Farago. In the past, lurbinectedin has been tested in combination with other chemotherapy drugs, such as doxorubicin and paclitaxel, and has shown some signal of activity in this patient population.

In the trial presented at the 2019 ASCO Annual Meeting, investigators evaluated the use of single-agent lurbinectedin in 105 patients with an ECOG performance score ranging from 0 to 2, who had received 1 prior line of chemotherapy treatment.

Final results from the trial showed a confirmed overall response rate of 35.2% (95% CI, 26.2-45.2), which surpassed the trial’s primary endpoint of at least 30%, says Farago. Compared with what has been observed in other trials with either topotecan or amrubicin, the observed response rate with lurbinectedin is high and very encouraging, she adds.

The key secondary endpoints examined in the trial included median duration of response, median progression-free survival, and median overall survival, adds Farago, which were 5.3 months, 3.9 months, and 10.8 months, respectively. Again, in comparison with other recent randomized studies that have read out, the data are promising and may be suggestive of significant clinical activity.

Although these results are encouraging, Farago cautions that a limitation is that it was a single-arm study. Farago hopes to have randomized phase III trial data on this agent in the future.

Anna F. Farago, MD, PhD, assistant professor of medicine at Harvard Medical School, discusses the phase II trial results using the marine-based drug lurbinectedin as a single agent treatment inpatients with small cell lung cancer.

Dr. Farago on Effectiveness of Single-Agent Lurbinectedin in SCLC

Anna F. Farago, MD, PhD, attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, discusses patient eligibility criteria for frontline immunotherapy in small cell lung cancer (SCLC).

The National Comprehensive Cancer Network guidelines list the combination of atezolizumab (Tecentriq) with carboplatin and etoposide as a category 1 recommended and preferred regimen for patients with extensive-stage SCLC, says Farago. However, data from the phase III IMpower133 trial, which served as the basis for the regimen’s approval, did not reflect patients with active autoimmune diseases, as they were excluded from the trial. There is concern about the risk of autoimmune disease flares or other autoimmune complications for patients with an autoimmune condition. However, the risk depends on the severity of the disorder or history therein. An autoimmune disorder does not disqualify a patient from receiving a checkpoint inhibitor, explains Farago.

The other population that was excluded from the trial was patients with untreated brain metastases. Similarly, untreated brain metastases do not disqualify a patient from immunotherapy. Rather, the decision comes down to clinical judgement. It's not uncommon that patients with SCLC present with small asymptomatic brain metastases. Historically, these patients receive standard carboplatin and etoposide and are followed closely. The same approach could be taken with the addition of atezolizumab, says Farago. However, these patients are likely to require whole-brain radiation at some point in their treatment, which warrants additional consideration.

Dr. Farago on Eligibility Criteria for Frontline Immunotherapy in SCLC

Anna F. Farago, MD, PhD, assistant professor of medicine at Harvard Medical School, discusses the FDA approval of single-agent pembrolizumab for the frontline treatment of patients with stage III non—small cell lung cancer (NSCLC), who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression (tumor proportion score) level of ≥1% and do not harbor 

Anna F. Farago, MD, PhD, assistant professor of medicine at Harvard Medical School, discusses the FDA approval of single-agent pembrolizumab for the frontline treatment of patients with stage III non–small cell lung cancer, who are ineligible for surgery or definitive chemoradiation, or metastatic NSCLC, with a PD-L1 expression (tumor proportion score) level of ≥1% and do not harbor EGFR or ALK aberrations.

Anna F. Farago, MD, PhD

Articles

Dr. Farago on Frontline Immunotherapy Versus Maintenance Immunotherapy in SCLC

Dr. Farago on Effectiveness of Single-Agent Lurbinectedin in SCLC

Dr. Farago on Eligibility Criteria for Frontline Immunotherapy in SCLC

Dr. Farago on the FDA Approval of Pembrolizumab for Lower PD-1 Cutoff NSCLC